Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-β

Abstract

Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

Predictors of Rapid Cognitive Decline in Patients with Mild-to-Moderate Alzheimer Disease: A Prospective Cohort Study with 12-Month Follow-Up Performed in Memory Clinics

“…Certain factors can be used to predict RCD, including moderate dementia at the time of treatment onset; vascular risk factors; a younger age; a higher level of education [33]; and the early appearance of hallucinations, psychosis, or extrapyramidal symptoms [34]. Possible biological explanations of variability in the rate of AD-related dementia progression include pathological changes in the blood vessels and the limbic and neocortical structures [35], and (perhaps) the development of distinct amyloid structures [36]. Some evidence indicates that certain genetic biomarkers accelerate the progression of cognitive decline in those with AD-related dementia [37].…”

The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease

“…The existence of variant structural strains of Ab is increasingly well established (Eisenberg and Jucker 2012;Lu et al 2013;Hatami et al 2014;Spirig et al 2014;Cohen et al 2015). Growing evidence supports the hypothesis that Ab seeds, like PrP prions (Aguzzi et al 2007;Collinge and Clarke 2007;Prusiner 2013), can also adopt different molecular conformations that are linked to their functionality in vivo (MeyerLuehmann et al 2006;Eisenberg and Jucker 2012;Stöhr et al 2014;Watts et al 2014).…”

High-speed atomic force microscopy reveals structural dynamics of amyloid β 1–42 aggregates

“…Fibrils are polymorphic-Aβ forms fibrils with distinct structures depending on experimental conditions (35,36). Additionally, different fibril types have different impacts on neurodegeneration (26,33,(37)(38)(39). Thus, characterization of the structural dynamics of the fibril formation process is an important endeavor.…”